Prader-Willi syndrome (PWS) is a complex, genetic neurodevelopmental disorder characterized by intellectual disabilities; compulsivity; tantrums; irritability; growth hormone dysfunction; hyperphagia; and increased risks of morbid obesity, psychosis, and autism spectrum disorders (ASD). Caused by a lack of paternally-derived imprinted material on 15q11-q13, Prader-Willi syndrome (PWS) remains a life-threatening and extremely challenging disorder for families to manage. This renewal builds on our success over the last grant period by identifying differential developmental trajectories based on Type I, Type II, and maternal UPD genotypes of PWS; examining other factors that impact these trajectories; and refining how we measure psychiatric outcomes across age. Over the next 5 years, we will follow 168 people with PWS aged 4 years through adulthood using a longitudinal, random coefficients slope-as-outcome model. Aim 1 identifies the lifespan trajectories of IQ, adaptive skills, hyperphagia, and psychopathology within the three main PWS genotypes. We expect that: Type I deletion cases will decline in IQ, adaptive skills and behavior problems; Type II cases will remain relatively stable; and those with mUPD will worsen psychiatrically but at the same time improve cognitively. Differences between Type I and Type II trajectories will relate to the expression of specific genes such as CYFIP1. Aim 2 examines other factors that impact trajectories, including the unstudied, non-body composition effects of growth hormone treatment, fluctuations in degree of obesity, and serotonin-altering genes (e.g., TPH-2, 5HTTLPR). Aim 3 refines how psychiatric outcomes in PWS are measured in trajectories by including but moving beyond psychiatric diagnoses (e.g., ASD, depression, psychosis) and identifying, for the first time, specific symptoms of these disorders, and those social, cognitive, and neural processes that are associated with these symptoms. Trajectories across the lifespan are more accurate than cross-sectional approaches, and analyses of trajectories will shed new light on differences across PWS genotypes, risks for ASD or psychosis, and how and when to best intervene to reduce problems and enhance positive outcomes in this syndrome. PUBLIC HEALTH RELEVANCE: Prader-Willi syndrome (PWS) is characterized by intellectual disabilities, compulsivity, hyperphagia, and increased risks of morbid obesity, psychosis, and autism spectrum disorders. Although PWS may be viewed as an alternative lens into these widespread problems, this grant also proposes studies that will lead to improved quality of life for persons with PWS and their families.